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Mady Slater, M.D. Stanford University Medical Center Division of Infectious Diseases

IGRAs for latent TB diagnosis- what are they and how do we interpret them?. Mady Slater, M.D. Stanford University Medical Center Division of Infectious Diseases Curry International TB Center June 21, 2014 Border Health Training.

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Mady Slater, M.D. Stanford University Medical Center Division of Infectious Diseases

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  1. IGRAs for latent TB diagnosis- what are they and how do we interpret them? Mady Slater, M.D. Stanford University Medical Center Division of Infectious Diseases Curry International TB Center June 21, 2014 Border Health Training

  2. I do not have any financial arrangements or affiliations with commercial sponsors which have direct interest in the subject matter: IGRA or TST.

  3. Does your program provide LTBI evaluation and/or treatment? • Yes, evaluation only • Yes, evaluation and treatment • No, neither evaluation or treatment, referral to provider • Other

  4. If your program provides LTBI evaluation, what test is used? • TST only • QFT only • T-spot only • QFT/T-spot and TST • Other

  5. Objectives At the end of this session, participants will be able to: · Identify the two primary IGRAs used in the US and describe how they are utilized and interpreted to accurately diagnose TB infection · Describe performance characteristics of IGRAs and compare to those of the TST to choose the best testing modality for their patient population · Summarize guidelines on the usage of IGRAs and discuss scenarios in which these test results may inform clinical decisions

  6. US Tuberculosis epidemiology in foreign born-2013 (MMWR) • FB cases – 64.6% of TB cases in the US (6172/9588); 20% of these from Mexico • The proportion of TB among the FB is increasing • FB rate 13-times rate of U.S.-born persons (1.2 vs. 15.6)

  7. Why is latent TB infection important? Goal of TB elimination= <1 case per million • Current US status: • Overall 30 cases per million • US born 14 cases per million • Hispanic 50 cases per million • Estimated that ~85% of active TB cases in foreign born are secondary to progression from LTBI • Modeling studies clearly show latent TB (LTBI) identification and treatment is an essential component of reaching the elimination goal. Trends in Tuberculosis-US 2013, MMWR Ricks et al, Plos one, 2011 Hill et al, Epidemiol Infect, 2012

  8. Pathogenesis of Tuberculosis Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis

  9. TB Pathogenesis- 3 outcomes:#1: Immune clearance#2: Latent TB Infection (LTBI) • Within 2 to 8 weeks macrophagessurround thepathogen and form a granuloma • These cells form a barrier that keeps the bacilli contained and under control (LTBI) • Not infectious Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis

  10. TB Pathogenesis- 3 outcomes:#3: TB Disease • If the immune system CANNOT keep tubercle bacilli under control, bacilli multiply and cause disease • Can occur at any time, with LTBI 5-10% lifetime risk • Infectious Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis

  11. LTBI vs. TB Disease Module 1 – Transmission and Pathogenesis of Tuberculosis

  12. Targeted TB testing • Screening should be targeted to those at  higher risk of TB-individuals with: • Increased rates of recent TB infection And/or 2. Increased risk of progression to active TB • Goals:  – Identify active TB cases – Identify LTBI that would benefit from treatment – Surveillance

  13. Targeted TB Testing **If no risk, don’t order the test- increased risk of false positives.**

  14. TB risk screen includes: • Prior TB infection/disease, treatment • Prior TB testing • TB symptom review • Medical conditions / risk factors • Sociodemographic factors • HIV status

  15. LTBI Testing -No “gold standard” since there is no way to microbiologically diagnose LTBI -Must use proxy of the host immunologic response to TB antigens to infer the diagnosis

  16. Diagnosis of LTBI from 1908 to Dec 2006 • - TST •  Disadvantages • Subjective • Logistic tracking difficulties • - In vivo • - Adverse effects • - Boosting • - Affected by BCG • and non-tuberculous • mycobacteria • - Requires two visits

  17. IGRAs entered the scene in 2006-2007 with a lot of promise (blood test using more specific TB antigens than TST) ‘A 21st Century Solution for Latent TB Detection’

  18. Many medical centers have switched to IGRAs for LTBI screening  QFT-GIT Advantages -1 step testing -Automated (ease of surveillance) -Improved specificity in BCG vaccinated and individuals with non-tuberculousmycobacterial infection -Likely more cost-effective -No boosting QFT-GIT Disadvantages -Blood draw -Performance data in long term studies lacking -Caution in young children, immunocompromised/HIV -Serial testing showing high variability

  19. TST Interpretation ATS/CDC guidelines 2000

  20. IGRA Interpretation T-SPOT- Elispot detects activated memory T cells QFT-ELISA quantifies IFN-gamma Memory T cell Antigen presenting cell CD4 + IFN- APC ESAT6 CFP-10 TB7.7 * (TB Ag - Nil) and assumes appropriate control responses

  21. What is the QFT assay? • The QFT assay is comprised of 3 tubes: -Antigen: inside of tube is coated with TB-specific antigens -Nil: contains heparin and serves as a negative control. -Mitogen: contains phytohaeamagluttinin (PHA) and serves as positive control providing information about correct blood sample handling and the immune status of pt • ELISA is performed in all 3 tubes to measure the Interferon-gamma level (IU/ml) ***QFT result (IU/ml)= Antigen-Nil***

  22. How do IGRAs perform? • Key performance characteristics of any diagnostic: -Sensitivity (true positive proportion identified) -Specificity (true negative proportion identified) • HOWEVER, ability to assess performance limited by lack of gold standard for LTBI diagnosis -Most accepted method is testing populations with known characteristics (ie active TB patients for sensitivity estimates and low risk individuals for specificity estimates)

  23. Accuracy of the current LTBI diagnostics • Mazurek MMWR 2010.

  24. CDC 2010 MMWR IGRA Recommendations IGRA preferred • Persons with likely poor return rate for TST reading • Persons who have received BCG vaccine

  25. CDC 2010 MMWR IGRA Recommendations IGRA or TST recommended  (without preference) • Recent contacts to person infected with TB • Periodic screening of HCWs

  26. CDC 2010 MMWR IGRA Recommendations TST preferred  (IGRA acceptable) • Children <5 years

  27. Should I test with both a TST and IGRA? Not recommended! However, cases where it can be helpful: If the initial test is negative AND •  high risk of infection, progression, or poor outcomes  (HIV positive, < 5 years of age, immunocompromised) – If the initial test is positive AND • There is need for additional evidence to encourage compliance •It is a healthy person with low risk of both infection and progression

  28. TST vs. IGRA: What to do with discordant results • Avoid using two tests for TB screening • TST(+) / IGRA(‐) – Foreign born with BCG and no severe immunocompromising  condition ‐ attribute to BCG - However, abnormal CXR consistent with old TB + risk factor for  progression to disease, consider treatment – U.S. born ‐ with no risk factors for exposure or risk factors for  progression may be NTM colonization

  29. TST vs. IGRA: What to do with discordant results • TST(‐) / IGRA(+) - If FB but no risk for TB progression: consider repeat IGRA if near cutoff point ie <0.7UL/ml *controversial -US born with no risk factors for exposure or progression- repeat IGRA ** If severe immunocompromising condition: and discordant TST/ IGRA OR TST/IGRA negative and abnl CXR c/w old TB, offer LTBI treatment

  30. Discordant results summary • Immunocompromised with infection risk: use any positive result (high risk with missing true LTBI) • BCG vaccinated and healthy: use IGRA • Low risk: shouldn’t be tested but negative result is more likely true. • Moderate risk: evaluate exposure and medical risk, assess risk-benefit of LTBI treatment

  31. What about indeterminates? (indeterminate = either a low positive control or a high negative control value) Per QFT Package insert: The 2 main causes of indeterminate results are due to technical errors (ie improper incubation, insufficient mixing of blood collection tubes) Other less common causes are: -Transient (viral illness, recent vaccination) -Chronic (immunosuppression)

  32. If the QFT result is indeterminate… • Repeat the test in ~3-4 weeks (can help if the indeterminate is secondary to technical problems or transient patient abnormality) • If the repeat is indeterminate, then IGRA can’t be used for clinical decision making, except to assume that the patient is probably anergic. • Other tests (ie TST), clinical information, TB risk factors and risk of progression must be used instead.

  33. IGRA and TST limitations • The CDC and WHO advises against the use of both IGRAs and TST for diagnosis of active TB. -~20% of individuals with active TB will have a negative IGRA or TST -So a negative IGRA/TST does NOT rule out active TB

  34. IGRA and TST limitations (cont.) • IGRAs/TST should NOT be used to monitor response to TB therapy; studies in this area are inconsistent. • IGRAs/TST can NOT accurately predict the risk of infected individuals developing active TB disease • IGRAs/TST can NOT distinguish old from new infection

  35. IGRAs: timing of conversions • Most IGRA conversions occur within four to eight weeks after exposure (similar to TST) • However, conversion after three months has been reported

  36. Conclusions • LTBI diagnosis is a combination of evaluation of risk factors for TB infection and risk of TB progression AND TST/IGRA results • IGRAs are logistically easier but interpretation is as equally challenging as the TST • IGRAs do have advantage in reducing false positives in BCG vaccinated individuals • Discordant TST/IGRA results do occur- if a person is immunocompromised, be conservative and err on the side of treatment • If an indeterminate IGRA result is obtained, repeat the test in 3-4 weeks • Do not use TST/IGRA results to monitor response to treatment for LTBI

  37. Acknowledgements Financial Support Stanford SPARK/ Global Health Curry International TB Center Kelly Musoke Ann Raftery Julie Higashi, MD, PhD Stanford University NiazBanaei, MD Upi Singh, MD Julie Parsonnet, MD McGill MadhukarPai, MD, PhD

  38. Does your program provide LTBI evaluation and/or treatment? • Yes, evaluation only • Yes, evaluation and treatment • No, neither evaluation or treatment, referral to provider • Other

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